Alzheimer's disease (or Alzheimer Disease, AD) is a common disorder of the elderly that currently affects over 5 million Americans. It is an incurable and progressive neurodegenerative senile disorder. Although the primary cause(s) of AD is unknown, the disease process involves the progressive extracellular accumulation of aggregated forms of amyloid β peptide (Aβ or Abeta) into plaques in the brain, and associated intracellular deposits of hyperphosphorylated tau protein and brain atrophy. AD patients exhibit progressive cognitive and emotional/behavioral impairments as a result of synaptic dysfunction and neuronal degeneration in multiple interconnected brain regions including the hippocampus, frontal cortex and amygdala.
Studies of experimental cell culture and animal models of AD suggest that the neurotoxic activity of Aβ occurs when Aβ is in an oligomeric form, and involves membrane-associated oxidative stress that impairs synaptic plasticity and memory and causes neuritic and tau hyperphosphorylation. The accumulation of Aβ can also trigger the induction of harmful inflammatory responses that involve the activation of microglia and astrocytes and cause infiltration of Aβ-specific T cells into the brain (Aβ contains a number of human and mouse T cell epitopes in its 15-42 amino acid portion), and may eventually lead to patho-neurophysiological impairments and death.
There is a great need for AD vaccines, especially for those that are effective in middle- to old-aged individuals. Preclinical studies have demonstrated that Aβ deposits can be reduced by passive administration of Aβ-specific antibody or by active immunization with Aβ(1-42) peptide. For example, in a clinical trial of active Aβ immunization (vaccine AN1792) in AD patients, generation of anti-Aβ antibody was associated with a slower rate of decline of cognitive functions in those patients. However, only about 70% of the test subjects were antibody responders, despite repeated immunizations. Although vaccines that reduce Aβ plaques can control AD, the rationale for their use at the onset of the disease remains debatable. For example, older humans and mice usually respond poorly to vaccines generally, due to an age-related decline in immunity and associated immunological impairments. Moreover, chronic exposure to Aβ may also induce AD vaccine or antibody hyporesponsiveness. This may explain the inability of 3×TgAD mice to generate antibody when immunized with Aβ(1-42) peptide, and the relatively poor response demonstrated in AD patients to AN1792. Safety concerns with prior vaccines may preclude the feasibility of AD immunizations in apparently healthy people prior to diagnosis/onset of AD. For example, an AN1792 vaccine trial was prematurely halted because a subset of patients developed T-cell mediated meningoencephalitis, attributed to the induction and infiltration of Aβ-specific T cells.
Accordingly, there is a continued need in the art for compositions and methods to safely prevent and/or slow the progress of AD and to improve the quality of life of sufferers.